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Chinese Medical Journal Mar 2024Cochlear spiral ganglion neurons (SGNs) are bipolar ganglion cells and are the first neurons in the auditory transduction pathway. They transmit complex acoustic...
Cochlear spiral ganglion neurons (SGNs) are bipolar ganglion cells and are the first neurons in the auditory transduction pathway. They transmit complex acoustic information from hair cells to second-order sensory neurons in the cochlear nucleus for sound processing. Injury to SGNs causes largely irreversible hearing impairment because these neurons are highly differentiated cells and cannot regenerate, making treatment of sensorineural hearing loss (SNHL) arising from SGN injury difficult. When exposed to ototoxic drugs or damaging levels of noise or when there is loss of neurotrophic factors (NTFs), aging, and presence of other factors, SGNs can be irreversibly damaged, resulting in SNHL. It has been found that NTFs and stem cells can induce regeneration among dead spiral ganglion cells. In this paper, we summarized the present knowledge regarding injury, protection, and regeneration of SGNs.
Topics: Humans; Spiral Ganglion; Neurons; Cochlea; Hearing Loss, Sensorineural; Hair Cells, Auditory
PubMed: 37407223
DOI: 10.1097/CM9.0000000000002765 -
Molecular Therapy. Nucleic Acids Mar 2024Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity is closely related...
Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity is closely related to the accumulation of reactive oxygen species (ROS) and subsequent death of hair cells (HCs) and spiral ganglion neurons (SGNs). Despite various strategies to combat ototoxicity, only one therapeutic agent has thus far been clinically approved. Therefore, we have developed a gene therapy concept to protect cochlear cells from cisplatin-induced toxicity. Self-inactivating lentiviral (LV) vectors were used to ectopically express various antioxidant enzymes or anti-apoptotic proteins to enhance the cellular ROS scavenging or prevent apoptosis in affected cell types. In direct comparison, anti-apoptotic proteins mediated a stronger reduction in cytotoxicity than antioxidant enzymes. Importantly, overexpression of the most promising candidate, achieved an up to 2.5-fold reduction in cisplatin-induced cytotoxicity in HEI-OC1 cells, phoenix auditory neurons, and primary SGN cultures. BCL-XL protected against cisplatin-mediated tissue destruction in cochlear explants. Strikingly, application of the LV BCL-XL vector improved hearing and increased HC survival in cisplatin-treated mice. In conclusion, we have established a preclinical gene therapy approach to protect mice from cisplatin-induced ototoxicity that has the potential to be translated to clinical use in cancer patients.
PubMed: 38450280
DOI: 10.1016/j.omtn.2024.102157 -
Neurotoxicology Jan 2024Cobalt is widely used in the medical industry, mainly including cobalt alloy joint implants and cobalt-chromium porcelain crowns. However, unexplained ototoxicity and...
Cobalt is widely used in the medical industry, mainly including cobalt alloy joint implants and cobalt-chromium porcelain crowns. However, unexplained ototoxicity and neurotoxicity often occur in the clinical use of cobalt agents at present, which limits the development of the cobalt industry. In this study, based on the clinical problem of cobalt ototoxicity, we first conducted an extensive search and collation of related theories, and on this basis, prepared an HEI-OC1 cell model and basilar membrane organotypic cultures after cobalt treatment. We used immunofluorescence staining, western blot, CCK8, and si-RNA to investigate the mechanism of cobalt ototoxicity, to discover its potential therapeutic targets. After comparing the reactive oxygen species, mitochondrial transmembrane potential, apoptosis-related protein expression, and cell viability of different treatment groups, the following conclusions were drawn: cobalt causes oxidative stress in the inner ear, which leads to apoptosis of inner ear cells; inhibition of oxidative stress and apoptosis can alleviate the damage of cobalt on inner ear cells; and the Dicer protein plays a role in the mechanism of inner ear damage and is a potential target for the treatment of cobalt-induced inner ear damage. Taken together, these results suggest that cobalt-induced ototoxicity triggered by oxidative stress activates a cascade of apoptotic events where cCaspase-3 decreases Dicer levels and amplifies this apoptotic pathway. It may be possible to prevent and treat cobalt ototoxicity by targeting this mechanism.
Topics: Apoptosis; Cisplatin; Cobalt; Cochlea; Microphysiological Systems; Ototoxicity; Reactive Oxygen Species; Animals; Mice; Cell Line
PubMed: 38101458
DOI: 10.1016/j.neuro.2023.12.009 -
BioRxiv : the Preprint Server For... Jun 2024Cisplatin is a commonly used chemotherapy agent with a nearly universal side effect of sensorineural hearing loss. The cellular mechanisms underlying cisplatin...
Cisplatin is a commonly used chemotherapy agent with a nearly universal side effect of sensorineural hearing loss. The cellular mechanisms underlying cisplatin ototoxicity are poorly understood. Efforts in drug development to prevent or reverse cisplatin ototoxicity have largely focused on pathways of oxidative stress and apoptosis. An effective treatment for cisplatin ototoxicity, sodium thiosulfate (STS), while beneficial when used in standard risk hepatoblastoma, is associated with reduced survival in disseminated pediatric malignancies, highlighting the need for more specific drugs without potential tumor protective effects. The unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways have been shown to be involved in the pathogenesis of noise-induced hearing loss and cochlear synaptopathy in vivo, and these pathways have been implicated broadly in cisplatin cytotoxicity. This study sought to determine whether the UPR can be targeted to prevent cisplatin ototoxicity. Neonatal cochlear cultures and HEK cells were exposed to cisplatin and UPR-modulating drugs, and UPR marker gene expression and cell death measured. Treatment with ISRIB, a drug that activates eif2B and downregulates the pro-apoptotic PERK/CHOP pathway of the UPR, was tested in an in vivo mouse model of cisplatin ototoxicity and well as a head and neck squamous cell carcinoma (HNSCC) cell-based assay of cisplatin cytotoxicity. Cisplatin exhibited a biphasic, non-linear dose-response of cell death and apoptosis that correlated with different patterns of UPR marker gene expression in HEK cells and cochlear cultures. ISRIB treatment protected against cisplatin-induced hearing loss and hair-cell death, but did not impact the cytotoxic effects of cisplatin on HNSCC cell viability, unlike STS. These findings demonstrate that targeting the pro-apoptotic PERK/CHOP pathway with ISRIB can mitigate cisplatin ototoxicity without reducing anti-cancer cell effects, suggesting that this may be a viable strategy for drug development.
PubMed: 37905009
DOI: 10.1101/2023.10.17.562797 -
Frontiers in Molecular Neuroscience 2024Polystyrene nanoplastics are a novel class of pollutants. They are easily absorbed by living organisms, and their potential toxicity has raised concerns. However, the...
Polystyrene nanoplastics are a novel class of pollutants. They are easily absorbed by living organisms, and their potential toxicity has raised concerns. However, the impact of polystyrene nanoplastics on auditory organs remains unknown. Here, our results showed that polystyrene nanoplastics entered the cochlea of mice, HEI-OC1 cells, and lateral line hair cells of zebrafish, causing cellular injury and increasing apoptosis. Additionally, we found that exposure to polystyrene nanoplastics resulted in a significant elevation in the auditory brainstem response thresholds, a loss of auditory sensory hair cells, stereocilia degeneration and a decrease in expression of Claudin-5 and Occludin proteins at the blood-lymphatic barrier in mice. We also observed a significant decrease in the acoustic alarm response of zebrafish after exposure to polystyrene nanoplastics. Mechanistic analysis revealed that polystyrene nanoplastics induced up-regulation of the Nrf2/HO-1 pathway, increased levels of malondialdehyde, and decreased superoxide dismutase and catalase levels in cochlea and HEI-OC1 cells. Furthermore, we observed that the expression of ferroptosis-related indicators GPX4 and SLC7A11 decreased as well as increased expression of ACLS4 in cochlea and HEI-OC1 cells. This study also revealed that polystyrene nanoplastics exposure led to increased expression of the inflammatory factors TNF-α, IL-1β and COX2 in cochlea and HEI-OC1 cells. Further research found that the cell apoptosis, ferroptosis and inflammatory reactions induced by polystyrene nanoplastics in HEI-OC1 cells was reversed through the pretreatment with N-acetylcysteine, a reactive oxygen species inhibitor. Overall, our study first discovered and systematically revealed the ototoxicity of polystyrene nanoplastics and its underlying mechanism.
PubMed: 38440220
DOI: 10.3389/fnmol.2024.1345536 -
Journal of Controlled Release :... Jan 2024Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in...
Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in clinical settings is limited due to anatomical barriers in the inner ear and pharmacokinetic instability. To address this issue, we developed an injectable hydrogel called RADA-HRN-dexamethasone (RHD). The RHD hydrogel possesses self-anti-inflammatory properties and can self-assemble into nanofibrous structures, ensuring controlled and sustained release of dexamethasone in the local region. Flow cytometry analysis revealed that the uptake of FITC-conjugated RHD gel by hair cells increased in a time-dependent manner. Compared to free dexamethasone solutions, dexamethasone-loaded RHD gel achieved a longer and more controlled release profile of dexamethasone. Additionally, RHD gel effectively protected against the inflammatory response, reduced excessive reactive oxygen species production, and reversed the decline in mitochondrial membrane potentials induced by ionizing radiation, leading to attenuation of apoptosis and DNA damage. Moreover, RHD gel promoted the recovery of outer hair cells and partially restored auditory function in mice exposed to ionizing radiation. These findings validated the protective effects of RHD gel against radiation-induced ototoxicity in both cell cultures and animal models. Furthermore, RHD gel enhanced the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which was inhibited by ionizing radiation, thereby promoting the survival of hair cells. Importantly, intratympanic injections of RHD gel exhibited excellent biosafety and do not interfere with the anti-tumor effects of radiotherapy. In summary, our study demonstrates the therapeutic potential of injectable dexamethasone-loaded RHD hydrogel for the treatment of radiation-induced hearing loss by regulating the mTOR signaling pathway.
Topics: Mice; Animals; Dexamethasone; Hydrogels; Reactive Oxygen Species; Ototoxicity; Signal Transduction; TOR Serine-Threonine Kinases; Mammals
PubMed: 38065412
DOI: 10.1016/j.jconrel.2023.12.004 -
BMC Cancer Nov 2023Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell... (Randomized Controlled Trial)
Randomized Controlled Trial
Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE).
BACKGROUND
Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN.
METHODS
This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.
DISCUSSION
If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT.
TRIAL REGISTRATION
This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 ( https://jrct.niph.go.jp/latest-detail/jRCTs031210100 ). Date of Registration: May 2021.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Cisplatin; Carcinoma, Squamous Cell; Quality of Life; Head and Neck Neoplasms; Neoplasm Recurrence, Local; Chemoradiotherapy
PubMed: 37932681
DOI: 10.1186/s12885-023-11503-z -
Seminars in Hearing Nov 2023This study aimed to scope the literature, identify knowledge gaps, appraise results, and synthesize the evidence on the audiological evaluation of workers exposed to... (Review)
Review
This study aimed to scope the literature, identify knowledge gaps, appraise results, and synthesize the evidence on the audiological evaluation of workers exposed to solvents. We searched Medline, PubMed, Embase, CINAHL, and NIOSHTIC-2 up to March 22, 2021. Using Covidence, two authors independently assessed study eligibility, risk of bias, and extracted data. National Institute of Health Quality Assessment Tools was used in the quality evaluation of included studies; the Downs and Black checklist was used to assess the risk of bias. Of 454 located references, 37 were included. Twenty-five tests were studied: two tests to measure hearing thresholds, one test to measure word recognition in quiet, six electroacoustic procedures, four electrophysiological tests, and twelve behavioral tests to assess auditory processing skills. Two studies used the Amsterdam Inventory for Auditory Disability and Handicap. The quality of individual studies was mostly considered moderate, but the overall quality of evidence was considered low. The discrepancies between studies and differences in the methodologies/outcomes prevent recommending a specific test battery to assess the auditory effects of occupational solvents. Decisions on audiological tests for patients with a history of solvent exposures require the integration of the most current research evidence with clinical expertise and stakeholder perspectives.
PubMed: 37818148
DOI: 10.1055/s-0043-1769585 -
Cureus Aug 2023Introduction The study aims to determine the role of intratympanic dexamethasone (ITD) on the hearing profile of patients with head and neck cancer...
Introduction The study aims to determine the role of intratympanic dexamethasone (ITD) on the hearing profile of patients with head and neck cancer post-chemoradiotherapy. Study design This study employs a prospective case-control design. Subjects and methods In total 834 patients were evaluated for eligibility. Seven hundred and eleven were excluded because they didn't meet the inclusion criteria. A hundred cases out of 123 were diagnosed with head and neck cancer for which the treatment protocol included cisplatin concurrent to radiotherapy recruited. Before each cisplatin treatment session, ITD was injected into one ear (experimental ear) while the other ear of the same patient served as the control. Pure-tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAE) test results of the baseline and follow-up examinations in the sixth and 12th weeks were compared within and between the study and control ears. Results For pure tone thresholds, significant hearing threshold change was noticed at 8 kHz in the experimental group at six weeks and at ≥ 6 kHz in the control group. At 12 weeks, high frequencies were significantly affected at ≥ 4 kHz in the control group. When the baseline was compared across the groups in the 12th week, for otoacoustic emissions, high frequencies showed a loss in the control group more compared to the experimental side (Wilcoxon signed-rank test). Conclusion ITD functions less effectively at higher frequencies because the basal turn of the cochlea is more susceptible to cisplatin ototoxicity. ITD might have potential in the reduction of cisplatin-induced hearing loss.
PubMed: 37779780
DOI: 10.7759/cureus.44299 -
Frontiers in Molecular Neuroscience 2024Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some... (Review)
Review
Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field - required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use - ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: (otic cell assays), (cochlear explant), and (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.
PubMed: 38756707
DOI: 10.3389/fnmol.2024.1379743